Concurrent TP53 and KRAS alterations show inconsistent survival impact across gastrointestinal cancers

Background: The tumor suppressor gene TP53 and the oncogene KRAS are among the most frequently altered core drivers in human malignancies. Although they cooperatively regulate critical biological processes, the prognostic impact of their co alterations remains poorly defined and exhibits striking inconsistency across different cancer types. Methods: We comprehensively analyzed genomic and clinical data from multi-cancer cohorts sourced from the cBioPortal database and The Cancer Genome Atlas (TCGA). Genetic alterations, including sequence variations and copy number alterations (CNAs), were classified for TP53 and KRAS. Patients were stratified into four subgroups based on individual or combined alteration status. Survival analyses were performed using Kaplan-Meier methods. Integrated multi-omics analyses were conducted to assess the relationship between genetic alterations and mRNA/protein expression, and to characterize co-occurring genetic events and their prognostic implications. Results: Patients harboring concurrent TP53 and KRAS alterations exhibited significantly shorter overall survival in pancreatic cancer, colorectal cancer, and ampullary carcinoma, but surprisingly demonstrated the longest survival in gastric cancer. Distinct KRAS mutation subtype distributions were observed across cancer types: G12D/G12V predominated in pancreatic and colorectal cancers, G12C in non small cell lung cancer, and G13D in gastric cancer, with copy number alterations representing a substantial proportion of KRAS alterations in gastric and lung cancers. Multi-omics analysis revealed a lack of concordance between genetic alterations and mRNA/protein expression, indicating that mutation status alone does not reliably reflect downstream molecular changes. Concurrent genetic events displayed striking cancer-type specificity: CDKN2A alterations frequently co-occurred with TP53/KRAS double alterations in pancreatic cancer and were associated with worse prognosis, whereas APC mutations co-occurred in colorectal cancer and correlated with improved survival. Integrated analysis further demonstrated that KRASaltered/TP53altered patients were highly enriched in pancreatic, colorectal, and lung cancers, each exhibiting unique background genomic landscapes. Conclusions: The prognostic significance of TP53 and KRAS alterations is profoundly cancer-type specific, driven by differences in mutation subtype distribution, copy number alteration patterns, co-occurring genetic events, and the discordance between genotype and functional expression. These findings challenge the simplistic view of dual-gene alterations as universal markers of poor prognosis and underscore the necessity of incorporating cancer-specific molecular contexts into prognostic models and precision oncology strategies.